Primary biliary cholangitis

Etiology

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• PBC is considered an autoimmune disease
• Often associated with other autoimmune conditions, e.g.:
  • CREST syndrome
  • Sicca syndrome
  • Autoimmune thyroid disease, especially Hashimoto thyroiditis
  • Celiac disease
  • Rheumatoid arthritis

Pathophysiology

Inflammation and progressive destruction (likely due to an autoimmune reaction) of the small and medium-sized intrahepatic bile ducts (progressive ductopenia) → defective bile duct regeneration → chronic cholestasis → secondary hepatocyte damage due to increased concentration of toxins that typically get excreted via bile → gradual portal and periportal fibrotic changes → liver failure → liver cirrhosis and portal hypertension (in advanced stage)

Clinical features

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Clinical features of PBC

Similar to PSC + xanthomas and xanthelasma

Patients with PBC are usually initially asymptomatic.

• Fatigue: most common and often the first symptom
• Marked pruritus: generalized
• Symptoms of cholestasis
  • Jaundice
  • Pale stool, dark urine
  • Maldigestion (more common in advanced disease)
    • Deficiency of fat-soluble vitamins (A, D, E, and K)
• Signs of cirrhosis and portal hypertension
  • Hepatomegaly with dull lower margin, RUQ discomfort
  • Splenomegaly
• Hyperpigmentation
  • Due to increased amounts of melanin; the exact cause and pathomechanism remain unclear.
• Xanthomas and xanthelasma

Diagnostics

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Autoimmune Liver Diseases

Mnemonic

• PBC: Boobs, Women get it (autoimmune + mitochondria from mom) → “Women stay inside” (intrahepatic ducts only).
• PSC: Scrotom, Men get it → “Men go wherever” (intra- and extrahepatic ducts) + p-ANCA (“perineuclear” → crude link to male anatomy).

Feature	Primary Sclerosing Cholangitis (PSC)	Primary Biliary Cholangitis (PBC)	Autoimmune Hepatitis (AIH)
Patho	Inflammation/fibrosis of intra- & extrahepatic bile ducts	Autoimmune destruction of intrahepatic bile ducts	Autoimmune destruction of hepatocytes
Epi / Assoc.	M > F (2:1), <40s Assoc: Ulcerative Colitis (IBD) (>80%)	F >> M (9:1), 40-60s Assoc: Sjögren’s, other autoimmune dz	F > M (3:1), bimodal (young/middle-aged) Assoc: Other autoimmune dz
Labs	Cholestatic: ↑↑ ALP, ↑ GGT	Cholestatic: ↑↑ ALP, ↑ GGT	Hepatocellular: ↑↑↑ AST/ALT (>1000s common), ↑ IgG
Serology	(+) p-ANCA	(+) AMA (Anti-Mitochondrial Ab)	(+) ANA, (+) ASMA (Anti-Smooth Muscle Ab)
Dx / Histo	MRCP/ERCP: “Beads on a string” Histo: “Onion skinning” periductal fibrosis	Normal imaging Histo: Florid duct lesion (lymphocytic cholangitis, granulomas)	Normal/nonspecific imaging Histo: Interface hepatitis, plasma cells
Tx	Symptomatic Tx; Liver transplant (definitive)	Ursodeoxycholic acid (UDCA)	Corticosteroids, Azathioprine
Key Risk	Cholangiocarcinoma, Colorectal Cancer (w/ UC)	Osteoporosis, Cirrhosis, HCC	Cirrhosis, Acute Liver Failure

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• Liver chemistries: cholestatic pattern of injury
  • ↑ ALP, ↑ GGT, ↑ direct bilirubin
  • Mild transaminitis (or normal AST and ALT)
• Lipid panel: hypercholesterolemia
• PBC-specific autoantibodies
  • Antimitochondrial antibodies (AMA) (present in > 95% of patients)
• Immunoglobulins (nonspecific)
  • ↑ IgM
• Biopsy
  • Because intrahepatic bile ducts are concentrated in the periportal regions, histopathology demonstrates periductal fibrosis predominantly in those regions.

Treatment

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General principles

• Start pharmacotherapy with ursodeoxycholic acid for all patients.
• Offer supportive care, including management of cholestasis-associated pruritus.
• Liver transplantation is necessary if liver cirrhosis is advanced.

Pharmacotherapy

• First-line: ursodeoxycholic acid (UDCA, ursodiol): a hydrophilic, nontoxic bile acid
  • Mechanism
    • Normal bile acid is hydrophobic. When bile ducts are blocked (as in PBC), these bile acids back up and start dissolving the membranes of the liver cells. When you take Ursodiol, it enters your system and eventually replaces up to 50% of the bile pool. It dilutes the “toxic” bile, making the mixture much less corrosive.
    • ↓ Cholesterol secretion into bile; makes bile less lithogenic.
    • Dissolves cholesterol stones.
  • Indications
    • Primary Biliary Cholangitis (PBC): First-line therapy (delays progression).
    • Gallstones: Medical dissolution of radiolucent (cholesterol) stones in poor surgical candidates.
    • Rapid weight loss: Prophylaxis against stone formation.
  • Adverse Effects
    • Diarrhea.